Silver-catalyzed C-C bond formation with carbon dioxide: Significant synthesis of dihydroisobenzofurans

Article abstract of DOI:10.1039/c3cc47221c

The silver salt catalyzed the C-C bond forming reaction of o-alkynylacetophenone derivatives and carbon dioxide. In this reaction, a carbonyl group and a furan skeleton were successively constructed to afford the corresponding dihydroisobenzofuran derivatives.

Full text of DOI:10.1039/c3cc47221c

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Silver-catalyzed C–C bond formation with carbon dioxide:
significant synthesis of dihydroisobenzofurans†
Cite this: Chem. Commun., 2013,
49, 11320
Kohei Sekine, Ayano Takayanagi, Satoshi Kikuchi and Tohru Yamada*
Received 21st September 2013,
Accepted 10th October 2013
DOI: 10.1039/c3cc47221c
www.rsc.org/chemcomm
The silver salt catalyzed the C–C bond forming reaction of o-alkynyl-
acetophenone derivatives and carbon dioxide. In this reaction, a
carbonyl group and a furan skeleton were successively constructed
to afford the corresponding dihydroisobenzofuran derivatives.
Carbon dioxide has drawn much attention as a C1 resource due
to its abundant supply from industries, low toxic properties and easy
handling.1 The Kolbe–Schmitt reaction, found in any organic
chemistry textbook, has been employed for the commercial
Fig. 1 Bioactive compounds bearing dihydroisobenzofuran structure.
production of salicylic acid. On the other hand, the transition- by the transition-metal-catalyzed cyclization has been
metal-catalyzed carboxylation reactions of various carbon achieved,4a,e, f,h,5g substituents of phthalans were limited and
nucleophiles have been actively researched for the preparation in some cases high temperature was required.
of fine chemicals.2 The synthesis of value-added chemicals,
Enolate has been a promising reagent for the C–C bond
for example medicinal supplies, agrichemicals and functional forming reactions. The reactions of carbon dioxide with an
materials, requires toxic C1 sources such as carbon monoxide enolate to produce the corresponding b-ketocarboxylic acid
and phosgene. In this paper, it was noted that instead of using have been examined.6 Due to its thermodynamic instability,
these toxic reagents, safe and inexpensive carbon dioxide could be however, the product would easily return back to the starting
effectively employed to produce dihydroisobenzofuran derivatives material. Therefore, careful treatment or subsequent reduction
which would be useful frameworks for synthesizing natural products of the product was required. A tandem reaction for the conver-
and medicines.
sion of b-ketocarboxylic acid into a stable compound is one of
Dihydroisobenzofuran(phthalan) is a class of characteristic the most reasonable methods for the reaction of an enolate and
structures used as a building block for natural product synthesis carbon dioxide.
or a key mother nucleus of significant bioactive compounds
Recently, we reported that the combination of a silver salt
(Fig. 1).3 For example, Pestacin displays antioxidant activity and and base effectively promoted the incorporation of carbon
moderate antifungal properties.3a Escitalopram is known as an dioxide into propargylic alcohols, propargylic amines and
antidepressant of the selective serotonin reuptake inhibitor o-alkynylanilines.7 In these reactions, the geometry of the
class.3b Compound 1 having a benzylidene structure shows a exo-olefin in every product was confirmed as the Z isomer by
potential tyrosine-kinase inhibitory effect.3c Among the various X-ray analysis or an NOE experiment. These results and DFT
synthetic reactions for the phthalan derivatives, the transition- calculations supported the fact that the alkyne activation by a
metal-catalyzed cyclization reactions of o-alkynylbenzylalcohol4 silver catalyst should be essential.7e The silver-catalyzed C–C bond
or o-alkynylbenzaldehyde5 are particularly useful with respect to forming reaction of alkyne-containing ketones and carbon dioxide
atom economy. In many cases, however, phthalan and isochromene was also successfully developed to provide the corresponding
were obtained through the 5-exo-dig and 6-endo-dig cyclizations, 5-membered ring lactone derivatives.8 Interestingly, during the
respectively. Though the selective synthesis of phthalan derivatives reaction optimization of the alkyne-containing aliphatic ketones,
not only the corresponding lactone derivatives, but also furan
derivatives containing a carboxyl group were detected. Based on
the structure of the furan, it was assumed that the ketone carbonyl
Department of Chemistry, Keio University, Hiyoshi, Kohoku-ku,
Yokohama 223-8522, Japan. E-mail: yamada@chem.keio.ac.jp
of the b-ketocarboxylic acid was trapped on the C–C triple bond
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3cc47221c
activated by the silver catalyst unlike in our previous studies.9
c
11320 Chem. Commun., 2013, 49, 11320--11322
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and AgOAc were used, in every case, the dihydroisobenzofuran
3a was exclusively produced via the 5-exo-dig cyclization
(Table 1, entries 5–7). Under a 1 atm (balloon) CO2 atmosphere,
this reaction also proceeded but a longer reaction time was
required (Table 1, entry 8). In DMF and DMSO, 3a was obtained
in 94% and 91% yields, respectively (Table 1, entries 9 and 10).
Other bases were also examined, but DBU was found to be the
most suitable base in this reaction.9 Unfortunately, the purifica-
tion of 3a was not successful using the standard methods, such
as back extraction and silica gel column chromatography,
though 3a could be isolated by recrystallization in 66% yield
(Table 1, entry 7). In order to obtain the corresponding ester of
3a, esterification was attempted. It was found that 3a could be
esterified with methyl iodide in a one-pot synthesis to give the
corresponding methyl ester 4a in 92% yield (Table 2).
The substrate scope of the silver-catalyzed cyclization under
the optimized reaction conditions was investigated (Table 2).
Substituents on the phenyl ring in the R1 group were evaluated.
The reactions of substrates having 4,5-OMe (2b), 4-F (2c), or
5-Cl (2d) were efficiently catalyzed to give the corresponding
products 4b–4d in high yields. As for 2e bearing 2-naphthylketone,
the product 4e was obtained in 69% yield. The reactions were
Scheme 1 Silver-catalyzed cyclization affords dihydroisobenzofuran derivatives.
This result inspired us to examine the C–C bond forming
reaction with carbon dioxide to successively construct a carboxyl
group and a furan skeleton. It was postulated that dihydro-
isobenzofuran derivatives bearing a carboxyl group could be
obtained by the 5-exo-dig regioselective cyclization of o-alkynyl-
acetophenone and carbon dioxide using the silver-catalytic system
(Scheme 1). In the literature, these compounds were synthesized
by the coupling–cyclization of 3-(2-iodophenyl)-3-oxopropanoic
acid derivatives and terminal alkynes10 or the functionalization
of 1-alkylidene-1,3-dihydroisobenzofurans,11 but the yields were
unsatisfactory or the scope of the substrates was limited. We now
report the silver-catalyzed C–C bond formation using carbon
dioxide to afford dihydroisobenzofuran derivatives via the 5-exo-dig
cyclization.
In an initial study, compound 2a was employed as a model
substrate and various metal salts were examined in the
presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in CH3CN
under a 1.0 MPa CO2 atmosphere (Table 1). In the absence of a
metal salt, a trace amount of the desired product 3a was
Table 2 Silver-catalyzed cyclization of various o-alkynylacetophenonesa
1
observed in the H NMR spectrum (Table 1, entry 1). Although
AuI, CuI, and PdII were expected to activate the C–C triple bond
to catalyze the cyclization reaction of o-alkynylbenzyl alcohol or
o-alkynylbenzaldehyde, these metals did not effectively work in
the present reaction (Table 1, entries 2–4). On the other hand,
when a catalytic amount of a AgI salt was employed, the
reaction smoothly proceeded to afford dihydroisobenzofuran
3a in an excellent yield (Table 1, entry 5). When AgNO3, AgBr
Table 1 Investigation of several metal salts and solvents
Entrya
Catalyst
Solvent
Yieldb/%
1
None
(PPh3)AuCl
CuBr
Pd(OAc)2
AgBr
AgNO3
AgOAc
AgOAc
AgOAc
AgOAc
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
o1
2
0
3c
4
7
3
89
5
6
91
7
99 (66)d
98
8e
9
94
91
10
DMSO
a
The reaction was carried out with 0.15 mmol of the substrate, 30 1C,
1 h. b Yields were determined by 1H NMR using trimethylphenylsilane as
the internal standard. c 21 h. d Isolated yield. Purified by recrystallization.
e Under a 1 atm (balloon) CO2 atmosphere, 24 h.
a
b
Isolated yield. The ratio of Z and E isomers about the C–C double
bond adjacent to the carbonyl group. Determined by 1H NMR.
c
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suitable when the phenyl ring in the R2 group was substituted
with p-Me (2f), p-CF3 (2g), p-COMe (2h), p-CHO (2i), and
o-CO2Me (2j) regardless of the electron-withdrawing or electron-
donating groups. The alkyl-substituted alkynes were also good
substrates, and the corresponding products 4k, 4l, and 4m were
obtained in 95%, 97%, and 94% yields, respectively. The reaction of
the substrate 2n bearing the terminal alkyne gave the corre-
sponding product 4n in 62% yield. The silver-catalyzed system
was applied to a-substituted ketones. However, even if the reaction
time was 24 h, substrate 2o was not completely transformed and
produced the product 4o in only 51% yield. Aprotic polar solvents
were examined expecting the effective solvation to promote the
generation of the enolate. As a result, DMSO was found to be
suitable as the solvent to afford the product 4o in the highest yield.
The reaction of substrates 2o–2q in DMSO afforded the corre-
sponding products 4o–4p in 73%, 55% and 47% yields, respec-
tively. For the purified products 4k–4n, as for the geometry of the
C–C double bond adjacent to the carbonyl group, Z/E isomers were
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It is noted that the silver-catalyzed system effectively promoted
the C–C bond forming reaction of the o-alkynylacetophenone
derivatives and carbon dioxide to afford the dihydroisobenzofuran
derivatives bearing a carboxyl group or a methoxycarbonyl group in
high-to-excellent yields. Furan derivatives were selectively obtained
via the 5-exo-dig cyclization. Further investigations are currently
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Financial support from Keio University Doctorate Student
Grant-in-Aid Program was gratefully acknowledged.
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